Blood purification therapy of an extracorporeal circulation type has been widely used as a treatment method for improving a symptom by removing, from blood, etiologic materials and toxic waste products accumulated in the blood due to various causes. Blood treating membranes are each a separating membrane loaded in a blood treating device such as a blood dialyzer, a blood filtrating device, a blood component fractionator, or a plasma separator that is used in the extracorporeal circulation type blood purification therapy. At present, most of the membranes are blood treating membranes of a hollow fiber membrane type.
The membrane structure of blood treating membranes is roughly classified into a homogeneous membrane, which has no skin layer in any transverse section of the membrane and is dense as a whole, and an inhomogeneous membrane, which is composed of a skin layer (dense layer) as a separation function region and a supporting layer as a reinforcing region. Furthermore, the inhomogeneous membrane is roughly classified into a symmetric membrane and an asymmetric membrane. Such a membrane structure is appropriately designed in accordance with a specific usage of the membrane. In the case of a blood dialyzer, which is a typical example of blood treating devices from the viewpoint of the percentage in the quantity thereof or product-varieties thereof, great importance is placed on the balance between diffusing performance and filtrating performance in order to improve the performance of the dialyzer. As a means for embodying very high diffusing performance and filtrating performance, an asymmetric porous structure is often adopted as the membrane structure thereof.
As the material of blood treating membranes, a membrane material made mainly of a polymer has been used, examples of the polymer including cellulose-, cellulose acetate-, polyamide-, polyolefine-, polyacrylonitrile- and polysulfone-based polymers. In particular, polysulfone-based polymer is excellent in film-forming performance as well as biological safety or chemical stability. The polymer can be designed to have various permeabilities or membrane structures. In recent years, therefore, the polymer has been rapidly spreading as a membrane material of blood treating membranes.
Such a membrane structure and membrane material have been combined to make investigations into various porous hollow fiber membranes for treating blood in which polysulfone-based polymer is used. As described above, in particular, as to a blood dialyzer, for reasons related to the size of materials to be separated, it is necessary not only to pay attention to the filtrating performance as in other blood treating devices, but also to keep a delicate balance between the diffusing performance and the filtrating performance. For the purpose, the shape of its vessel is an important factor; however, a basic factor therefor is the fractionation property inherent in the membrane thereof.
In general, the fractionation property of a membrane is an index for the degree of sorting into components to be caused to permeate through the membrane and components to be inhibited from permeating therethrough, and which is obtained as the comprehensive results of all separation principles including diffusion, filtration, adsorption and the like.
In the case of a hollow fiber membrane for blood dialysis, the fractionation property is an index for the degree to which low molecular weight proteins, such as β2-micro globulin which is a uremic toxins and is one of targets to be removed by dialysis treatment, are caused to permeate and remove at a high ratio while an albumin, which is a useful protein having a small difference in molecular weight from the above-mentioned proteins and should be kept in dialysis treatment, is restrained from permeating through the membrane. The height of the fractionation property, which may be referred to as the sharpness thereof, is an important performance required for blood treating membranes. Known are a large number of polysulfone-based porous hollow fiber membranes in which the fractionation property is improved from the viewpoint of the membrane structure, the production process and other various points (for example, Patent Documents 1 and 2). However, none of the membranes has as sharp a fractionation property as a living kidney. Thus, a further technical improvement has been desired.
In the meantime, porous hollow fiber membranes for treating blood are generally smaller in inside and outside diameters and membrane thickness than industrial hollow fiber membranes, and thus mechanical properties thereof are never high. As a result, even if a blood-treating porous hollow fiber membrane is sufficient for ordinary blood treatment, the membrane may be mechanically damaged by some factors. Usually, a careful attention is paid to the handling thereof; however, for example, when hollow fiber membranes are inserted, as a bundle, into a cylindrical vessel to fabricate a blood treating device, the hollow fiber membranes in the outer circumferential region of the bundle may be rubbed with the inner wall of the vessel to be bent. This causes a poor external appearance in the quality, or a poor flow of blood. It is therefore unavoidable to exclude the poor products from the producing process. Moreover, the effect of water introduced into a blood treating device is large; thus, in a wet type blood treating device, its hollow fiber membranes may be mechanically damaged by a high water flow rate, a high water pressure, the sloshing of water and the like during water filling step or during transferring after the water filling step. In a washing operation carried out in a therapy facility before the device is used, or in a washing step when the device is reused, the hollow fiber membranes may be affected by a high water flow rate or a high water pressure whether the device is of a wet type or of a dry type. The hollow fiber membranes may be cut away at worst by the high water flow rate or high water pressure, or the sloshing of water. In such a case, it is indispensable to remove the membranes in the production process, and to stop the use of the device so as to exchange the membranes in the therapy facility. Furthermore, when the device is used for treatment in the state that a trouble of the membranes is not detected in advance, blood may unfavorably leak to a greater or lesser extent.
The cause of mechanical damages of a hollow fiber membrane is firstly the fact that the diameter and the membrane thickness are very small. Physical properties inherent in a polymer of the membrane material or physical properties inherent in the hollow fiber membrane obtained therefrom are also largely concerned therein. It has been considered that, for example, an effect of the breaking strength or the breaking elongation of the hollow fiber membrane, as a mechanical property inherent in the membrane, is particularly large. In this manner, there is no escape from physical necessity that porous hollow fiber membranes for treating blood are mechanically damaged with ease while the membrane thickness is required to be made as small as possible from the viewpoint of designing a blood treating device into a compact form by making the permeability higher or making the bundle diameter small. Accordingly, an improvement in mechanical properties of hollow fiber membranes also continues to be a technically important theme.
Thus, attention is paid to recent techniques about mechanical properties, such as the strength, the elongation or the like, of high-performance hollow fiber membranes for purifying blood, in particular a polysulfone-based hollow fiber membrane. For example, Patent Document 3 describes that the strength of a membrane is improved by laying a supporting layer continuous with a dense layer, and Patent Document 4 states that an inclined structure of an asymmetric membrane is important for a sharp fractionation property. However, these descriptions are mere descriptions on a basic structure or a characteristic of an asymmetric membrane, which has been already generalized. Patent Document 5 states that a hollow fiber membrane having an asymmetric inclined structure and having a membrane thickness of 35 to 55 μm exhibits a high strength and a high elongation. However, this hollow fiber membrane is a membrane obtained by spinning an unstable membrane-forming raw spinning solution to which water has been added under a special condition of low-temperature coagulation, and is unclear about the degree of the fractionation property thereof and a specific membrane structure thereof.
Regarding these techniques, there are some techniques describing in more detail a relationship between the strength or the elongation of a hollow fiber membrane and the membrane structure. First, from a relatively macroscopic viewpoint, Patent Document 6 describes a network structure of a hollow fiber membrane-thickness section, which structure is made of a polysulfone with a covering layer made of polyvinylpyrrolidone (hydrophilizing agent). Patent Document 7 describes a relationship between a microscopic structure change due to a barus effect caused just below a spinning-out section and the elongation or fractionation property. Though these hollow fiber membranes are excellent in strength and elongation, any of the documents merely shows an example wherein the membrane thickness is 45 μm; it seems to be unavoidable that when the membrane is made thinner, mechanical properties thereof are lowered.
In contrast, Patent Documents 8 and 9 describe the so-called thinned polysulfone-based hollow fiber membrane which has a membrane thickness of 35 μm. However, any of these membranes are a homogeneous structure membrane in consideration of a relationship between the porosity of the membrane and the strength thereof, and those are not such a membrane structure as an asymmetric membrane structure which is carefully considered its diffusing performance.
In the meantime, from a viewpoint at a more microscopic molecular level, Patent Document 10 states that the bonding between polymers themselves is strengthened by optimizing the tension for spinning, so that a membrane having higher mechanical properties is obtained even when the membrane has the same porosity. Patent Document 11 states that when polyvinylpyrrolidone enters among polysulfone particles, the strength of the membrane is lowered. Although these hollow fiber membranes are excellent in strength and elongation, any of the documents merely shows an example of the membrane having a thickness of 45 μm, it seems to be unavoidable that when the membrane is thinned, mechanical properties thereof are lowered. About the relationship with the membrane structure, only an assumed mechanism is suggested. Details thereof are unclear. In contrast, Patent Documents 12 and 13 describe the so-called thinned polysulfone-based hollow fiber membrane which has a membrane thickness of 35 μm. However, the membrane described in Patent Document 12 is a homogeneous structure membrane although Patent Document 12 states that by sealing polyvinylpyrrolidone into a dense structure, the membrane is kept the elongation before and after the chemical treatment. Patent Document 13 states that the membrane density, more specifically the ratio of thickness between a dense layer and a coarse layer and others are concerned in the strength or the elongation of the membrane, and further states that when the content of polyvinylpyrrolidone is high, the skeleton of the membrane is softened, and it is advantageous for achieving the elongation. However, the resultant elongation is at most 46.3%. Thus, it cannot be said that a sufficiently high elongation is obtained. As described above, polyvinylpyrrolidone, which is a hydrophilizing agent, largely affects on the strength and the elongation of the polysulfone-based hollow fiber membrane, thus, the pyrrolidone is not necessarily preferred from the viewpoint of mechanical properties of the membrane. However, when polysulfone with high hydrophobicity is made suitable for blood treatment, it is very convenient to use polyvinylpyrrolidone as a hydrophilizing agent for various reasons. This makes it further difficult to make polysulfone-based hollow fiber membranes thinner.
As described above, the relationship between mechanical properties of a polysulfone-based hollow fiber membrane having an excellent fractionation property and the specific membrane structure thereof, has been mainly investigated in terms of the porosity, the density and homogeneity in structure. However, none of the obtained hollow fiber membranes could be satisfactory. As the membrane structure, for example, a fibril structure can be given from a viewpoint other than the above-mentioned viewpoints. Known are a technique referred to a relationship between a fibril structure of a membrane surface and the fractionation property thereof (Patent Document 14), and a technique referred to a relationship between a fibril structure of a membrane surface and the blood compatibility thereof (Patent Document 15). Also known is a technique referred to the homogeneity of a fibril structure in a thickness section of a membrane (Patent Document 16). However, nothing is known about an effect given to mechanical properties by such a microscopic structure. Accordingly, it has been expected as one direction to achieve further improvements by finding out newly relationships to which attention has not been paid hitherto between/among a membrane structure factor, mechanical properties, fractionation property and the like.
Patent Document 1: JP-A-H04-300636
Patent Document 2: JP-A-H10-243999
Patent Document 3: JP-B-H05-54373
Patent Document 4: JP-A-2003-33432
Patent Document 5: JP-A-2000-334281
Patent Document 6: JP-A-2005-58906
Patent Document 7: JP-A-2003-245524
Patent Document 8: JP-A-H10-109023
Patent Document 9: JP-A-H09-154936
Patent Document 10: WO 98/52683
Patent Document 11: JP-A-2003-154240
Patent Document 12: JP-A-H10-216488
Patent Document 13: JP-A-2005-342139
Patent Document 14: WO 2005/46763
Patent Document 15: JP-A-2005-87350
Patent Document 16: JP-A-H10-118472